We have identified persistent rubella in cutaneous granulomas in immunodeficient patients. This has critical implications for public health as well as for the immunodeficient population where the virus can cause destructive, disfiguring lesions. This application is designed to investigate the key T cell responses to rubella, the effect of rubella on macrophages, and to define the risk profile for the immunodeficient patients and the public health risks associated with long term persistence. Patients found to be positive for rubella in our initial study all had significant T cell compromise without having sufficient compromise to warrant a hematopoietic stem cell transplant, thus exposing them to the vaccine. We noted that the rubella capsid co-localized with macrophages that had markers of an M2 phenotype, a phenotype less focused on pathogen eradication and we hypothesize that rubella replicates better in M2 macrophages. Four sequenced viruses revealed two wild type revertant amino acid changes in all four viruses, suggesting that acquisition of mutations can contribute to persistence. Our model is that immunodeficiency delays clearance of the vaccine-strain rubella, which allows for the accrual of mutations. Persistence is associated with modulation of infected macrophages to the M2 phenotype and mutations in the T cell epitopes. Both contribute to viral escape from immune control. Infection of keratinocytes leads to altered morphology, increased cytokeratin, and ulceration associated with loss of keratinocyte integrity. One of our patients had persistence for over 20 years, and three patients had evidence of dissemination to other organs supporting our hypothesis of lack of immune control. To address this unexpected risk associated with vaccine-strain rubella, we have three Aims. The goal of Aim 1 is to better define the patient population at risk, identify other involved tissues, and sequence additional viruses. Analysis of two large datasets suggests that other tissues may be involved and additional types of immunodeficiencies. We will therefore extend our patient cohort to non-T cell immunodeficiencies and examine all sites of inflammation. We will define immune responses to rubella in immunodeficient patients in Aim 2. We will test T cell and B cell responses in rubella virus-positive and rubella virus-negative patients, comparing the immunodominant epitopes with mutated peptides. Interaction of rubella and M2 macrophages will be defined. Aim 3 is focused on public health risks associated with prolonged carriage of rubella. Shedding of mutated rubella virus could pose a significant risk to the general population. Additional specimens will be obtained from rubella-positive patients. We will also determine if T cells can be stimulated to respond to mutated rubella epitopes and test the hypothesis that treatment directed at T cell exhaustion can improve T cell responses. These three complementary Aims will dramatically improve our ability to identify patient populations at risk, define the immune effects of rubella, and determine risks to the general population.